New mutant monkeys model the inheritance of autism

Two members of a second generation of monkeys that inherited an autism-related trait from genetically modified parents. Photo by Liu et al. Nature (2015).

A new batch of genetically modified monkeys can reproduce features of autism, according to a study released today from researchers at the Chinese Academy of Sciences. By recreating elements of the disorder in lab primates, the scientists hope to generate an animal model that closely resembles the human condition. The team’s results only apply to one variety of autism, but such mutant monkeys could fill a major gap in the quest to understand autism spectrum disorders. Moreover, these GMO primates could serve as an unprecedented arena for testing new therapeutics.

One current barrier to cracking autism is a lack of animal models that precisely recreate what happens in humans. Most research has involved genetically altering rodents so they carry mutations linked to autism in people. But mice aren’t humans, so there are many limits to what these critters can teach about a complicated disorder like autism.

“Given that Autism Spectrum Disorder is [a] uniquely human disorder characterized by deficits in complex behaviors, there are limitations in relying solely on mouse models,” said University of California neuroscientist Melissa Bauman, who wasn’t involved in the new study. “Many pharmacological [drug] interventions developed in mice to treat human disease ultimately fail.”

Given monkeys are more closely related to humans, our primate cousins could offer a more faithful home for unpacking the brain circuits, behaviors and genetic traits responsible for human autism. Over the past four years, there have been whispers of scientists trying to create mutant monkeys by editing single genes. But genetic research in monkeys is notoriously difficult. For instance, monkeys typically produce one offspring at a time, so it can take years to rear large enough numbers for a study. Plus if a maturing fetus doesn’t like a scientifically introduced mutation, then it might spontaneously abort. Such events have hampered early attempts at creating mutant monkeys with autism traits.

In their new study, neuroscientist Zilong Qiu and his colleagues have not only tackled the tricky genetics associated with creating a primate model of autism, they’ve also accelerated the reproduction process, so it takes less time to create new generations of these autistic monkeys.

The team started by using a non-lethal virus to transport copies of a human gene — MECP2 — into the eggs of crab-eating macaques (Macaca fascicularis). Many different mutations in MECP2 have been linked to autism spectrum disorders in humans. One severe example is MECP2 duplication syndrome, wherein a person ends up with two copies of the gene. The condition is marked by speech problems, severe intellectual disability, developmental delays, seizures and muscle spasms and stiffness that become worse as a child tries to move.

Five years ago, Qiu and his team took these eggs with extra copies of MECP2, artificially inseminated them and then implanted the embryos in 19 surrogate monkey mothers. Half became pregnant, and in the spring of 2011, they birthed eight babies carrying the human version of MECP2. Most carried more than one copy of the introduced gene — one babe had seven copies.

The team tracked the behaviors of these mutant or “transgenic” monkeys as they grew up.

“The first cohort shows severe behavior related to human autism patients, including increased anxiety and most importantly a defect in social interactions,”said Qiu, who led the study from the Institute of Neuroscience at the Chinese Academy of Sciences in Shanghai.

At 1.5 years of age, the mutant monkeys avoided sitting in the same space as normal, age-matched monkeys. By three years of age, when puberty set in, mutant females struggled to share the same space as other mutant females, even if they had been reared together. The mutant monkeys also exhibited increased levels of repetitive motor behaviors, wherein they would endlessly circle their cage.

However, for the most part, the transgenic monkeys’ other cognitive functions were largely normal.

“Currently, we’re carrying out brain imaging studies to figure out which deficiencies in the brain circuits are responsible for this autism-like behavior,” Qiu said.

The team also found that their engineered MECP2 mutations could be inherited. Normally, it would take five or six years for a monkey to reach sexual maturity and breed a second generation, but the team accelerated the reproduction process. They extracted sperm from juvenile mutant monkeys and implanted it under the skin of mice to speed the maturation of the reproductive cells. Ten months later, mature sperm were extracted and used to artificially inseminate a new batch of surrogate mothers, producing a second generation of monkeys with autism-like social disorders.

“We’ve shortened the one-generation time from five to six years down to 2.5 years. That’s actually a great improvement in terms of generation time, potentially making monkey models more useful in the long run,” said Mu-ming Poo, director of the Institute of Neuroscience at the Chinese Academy of Sciences.

So should scientists toss out years of rodent-related autism research and make a fresh start in mutant primates? Nope. The findings from this investigation only provide clues to one rare variety of autism.

“Autism is an incredibly complex disease, and it does not have a single underlying biological cause. While it certainly has a genetic component to it, a full understanding of the genetics is still a long way away. Mutations in MECP2 and the duplication of MECP2 are only one of these myriad causes,” said University of Mississippi Medical Center evolutionary geneticist Eric Vallender, who wasn’t involved in the study.

However, the new study does offer a proof-of-concept that autism-related mutations can be successfully introduced to non-human primates. Future studies might ply other mutations linked to autism, yielding a haberdashery of mutant monkeys that express the broad spectrum of autism. Qiu says the researchers could use such animal models to identify autism-related brain circuits and test new therapeutics, such as gene editing tools like CRISPR, to tweak these nerve circuits. The world’s first customized monkeys using the breakthrough CRISPR system were reported nearly a year ago by a different Chinese group.

“That’s why we need to find out the genetic mutations that all kinds of autism patients have. For some particular mutations, we might be able to use gene editing to repair [the disorder],” said Qiu, whose findings are available in the journal Nature.

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